8 results on '"Sam XX"'
Search Results
2. The immunomodulatory role of paracrine signalling factor VSIG4 in peritoneal metastases.
- Author
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Chong YY, Thiagarajan S, Tan QX, Lim HJ, Tan JW, Hendrikson J, Ng G, Liu Y, Chong CYL, Guo W, Ngo NT, Leow WQ, Loh T, Sam XX, Lim TKH, Cai M, Seo CJ, Wong JSM, Soo KC, Chia CS, Shannon NB, and Ong CJ
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Gene Expression Regulation, Neoplastic, Immunomodulation, Paracrine Communication, Tumor Microenvironment immunology, Tumor-Associated Macrophages metabolism, Tumor-Associated Macrophages immunology, Colorectal Neoplasms pathology, Colorectal Neoplasms metabolism, Colorectal Neoplasms immunology, Peritoneal Neoplasms secondary, Peritoneal Neoplasms metabolism
- Abstract
Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
3. Comparison of an amplicon-based large panel next generation sequencing (NGS) assay with conventional testing methods for MET and HER2 amplification in lung and breast cancers.
- Author
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Tay TKY, Tan GS, Lee SH, Sam XX, Lim TH, Ng JWK, Tan DSW, and Lim TKH
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- Humans, Female, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, High-Throughput Nucleotide Sequencing, Gene Amplification, Lung metabolism, Breast Neoplasms diagnosis, Breast Neoplasms genetics
- Abstract
The frequency of MET and HER2 amplification being detected by next generation sequencing (NGS) is increasing due to NGS being increasingly adopted for molecular profiling of cancers. However, the accuracy of NGS in detecting these gene amplifications remains uncertain due to conflicting reports in the scientific literature. We studied the accuracy of an amplicon-based large panel NGS assay in detecting MET and HER2 amplification in lung and breast cancers, respectively, by comparing it against conventional testing methods. Amongst 48 lung cancers, four of five cancers that were MET amplified on fluorescence in situ hybridisation (FISH) were classified as amplified on NGS while 42 of the remaining 43 non-amplified cancers were classified as non-amplified on NGS, giving a sensitivity of 80%, specificity of 97.7% and overall concordance of 95.8%. Of the 46 breast cancers tested, only six of the nine cancers that were HER2-positive on immunohistochemistry (IHC)/FISH were HER2-positive on NGS, while all the remaining HER2-negative cases were negative on NGS, giving a sensitivity of 66.7%, specificity of 100% and overall concordance of 93.5%. All the false-negative cases had low level gene amplification (MET:CEP7 or HER2:CEP17 FISH ratio of <3). The low sensitivity for HER2 amplification may be confounded by the small sample size and disproportionate number of cases with low level amplification. In summary, the NGS assay has good concordance with conventional testing methods but may be less sensitive in detecting low level gene amplification., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
4. Soft Tissue Leiomyosarcoma With Microsatellite Instability, High Tumor Mutational Burden, and Programmed Death Ligand-1 Expression Showing Pathologic Complete Response to Pembrolizumab: A Case Report.
- Author
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Tay TKY, Yeong JPS, Chen EX, Sam XX, Lim JX, and Chan JY
- Subjects
- Antibodies, Monoclonal, Humanized, B7-H1 Antigen genetics, Humans, Leiomyosarcoma drug therapy, Microsatellite Instability
- Published
- 2022
- Full Text
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5. Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes.
- Author
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Tan GF, Goh S, Lim AH, Liu W, Lee JY, Rajasegaran V, Sam XX, Tay TKY, Selvarajan S, Ng CC, Teh BT, and Chan JY
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Prognosis, Transcriptome, Drug Resistance, Neoplasm physiology, Giant Cells pathology, Hemangiosarcoma pathology
- Abstract
Giant cells (GC) are a poorly understood subset of tumor cells that have been increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aimed to characterize the biological and clinical significance of GC in angiosarcoma, an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GC and compared with clinicopathological as well as NanoString gene expression data. GC were examined in angiosarcoma cell lines MOLAS and ISOHAS using conventional and electron microscopy, single cell whole genome profiling, and other assays. In the cell lines, GC represented a rare population of mitotically active, non-senescent CD31
+ cells, and shared similar genomic profiles with regular-sized cells, consistent with a malignant endothelial phenotype. GC remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GC were present in 24 of 58 (41.4%) cases. GC was correlated with poorer responses to chemotherapy (25.0% vs 73.3%, P = 0.0213) and independently contributed to worse overall survival outcomes (hazard ratio 2.20, 95% confidence interval 1.17-4.15, P = 0.0142). NanoString profiling revealed overexpression of genes, including COL11A1, STC1, and ERO1A, accompanied by upregulation of immune-related metabolic stress and metastasis/matrix remodeling pathways in GC-containing tumors. In conclusion, GC may contribute to chemoresistance and poor prognosis in angiosarcoma., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)- Published
- 2021
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6. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2.
- Author
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Ler LD, Ghosh S, Chai X, Thike AA, Heng HL, Siew EY, Dey S, Koh LK, Lim JQ, Lim WK, Myint SS, Loh JL, Ong P, Sam XX, Huang D, Lim T, Tan PH, Nagarajan S, Cheng CW, Ho H, Ng LG, Yuen J, Lin PH, Chuang CK, Chang YH, Weng WH, Rozen SG, Tan P, Creasy CL, Pang ST, McCabe MT, Poon SL, and Teh BT
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Gene Expression Regulation, Neoplastic, Insulin-Like Growth Factor Binding Protein 3 metabolism, Mice, Nude, Models, Biological, Neoplasm Invasiveness, Urinary Bladder Neoplasms pathology, Urothelium pathology, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Histone Demethylases metabolism, Nuclear Proteins metabolism, Polycomb Repressive Complex 2 metabolism, Transcription, Genetic, Urinary Bladder Neoplasms genetics
- Abstract
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A -null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A -null cell lines. EZH2 inhibition delayed tumor onset in KDM6A -null cells and caused regression of KDM6A -null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2., (Copyright © 2017, American Association for the Advancement of Science.)
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- 2017
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7. SETD2 histone modifier loss in aggressive GI stromal tumours.
- Author
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Huang KK, McPherson JR, Tay ST, Das K, Tan IB, Ng CC, Chia NY, Zhang SL, Myint SS, Hu L, Rajasegaran V, Huang D, Loh JL, Gan A, Sairi AN, Sam XX, Dominguez LT, Lee M, Soo KC, Ooi LL, Ong HS, Chung A, Chow PK, Wong WK, Selvarajan S, Ong CK, Lim KH, Nandi T, Rozen S, Teh BT, Quek R, and Tan P
- Subjects
- Case-Control Studies, Codon, Nonsense genetics, DNA Methylation genetics, Exome genetics, Gastrointestinal Stromal Tumors epidemiology, Gastrointestinal Stromal Tumors pathology, Histones genetics, Humans, Neoplasm Invasiveness, Phenotype, Prevalence, Prognosis, Severity of Illness Index, Singapore epidemiology, Biomarkers, Tumor genetics, Gastrointestinal Stromal Tumors genetics, Histone-Lysine N-Methyltransferase genetics, Mutation, Missense genetics
- Abstract
Background: GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients., Objectives: We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers., Designs: Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined., Results: High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10
-5 ). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10-5 )., Conclusions: Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)- Published
- 2016
- Full Text
- View/download PDF
8. Regulatory crosstalk between lineage-survival oncogenes KLF5, GATA4 and GATA6 cooperatively promotes gastric cancer development.
- Author
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Chia NY, Deng N, Das K, Huang D, Hu L, Zhu Y, Lim KH, Lee MH, Wu J, Sam XX, Tan GS, Wan WK, Yu W, Gan A, Tan AL, Tay ST, Soo KC, Wong WK, Dominguez LT, Ng HH, Rozen S, Goh LK, Teh BT, and Tan P
- Subjects
- Animals, Cell Proliferation, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, GATA4 Transcription Factor biosynthesis, GATA6 Transcription Factor biosynthesis, Gene Expression Profiling methods, Gene Silencing, Genetic Predisposition to Disease, Heterografts, Humans, Kruppel-Like Transcription Factors biosynthesis, Mice, Nude, Neoplasm Transplantation, Oncogenes genetics, Promoter Regions, Genetic, Stomach Neoplasms metabolism, Stomach Neoplasms pathology, Tumor Cells, Cultured, GATA4 Transcription Factor genetics, GATA6 Transcription Factor genetics, Gene Expression Regulation, Neoplastic genetics, Kruppel-Like Transcription Factors genetics, Stomach Neoplasms genetics
- Abstract
Objective: Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications., Design: KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice., Results: KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs., Conclusions: KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2015
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